Sodium channel blocker for treatment of loss of superficial sensitivity

ABSTRACT

The invention concerns a sodium channel blocker for the treatment of a reduction or loss of superficial sensitivity or sense of touch of a human being or another mammal

The invention concerns a sodium channel blocker for the treatment of ahuman being or another mammal and a pharmaceutical compositioncomprising that sodium channel blocker as well as method of treatment.

A sodium channel blocker is a compound that specifically binds to asodium channel in an axon of a neuron and specifically blocks thepassage of sodium ions through that sodium channel.

From WO 2006/032459 A1 the use of a sodium channel blocker and/or one ofits derivatives for the production of a medicament for the treatment ofperipheral-nervously derived neuropathic pain is known.

From WO 2007/110221 A1 the use of a sodium channel blocker and/or itsderivatives for the production of a medicament for the treatment ofneuropathic pain developing as a consequence of chemotherapy is known.

In many diseases such as diabetes mellitus or neuropathy the reductionor loss of superficial sensitivity or sense of touch is a problem. Itmay lead to painless severe infections and other painless wounds likeburns or cuts of which the patients remain unaware.

The problem to be solved by the present invention is to provide asubstance and a pharmaceutical composition as well as a method for thetreatment of a reduction or loss of superficial sensitivity or sense oftouch of a human being or another mammal

The problem is solved by the subject-matter of claims 1, 8 and 16.Embodiments of the invention are subject matter of claims 2 to 7, 9 to15 and 17 to 19.

According to the invention a sodium channel blocker (SCB) for thetreatment of a reduction or loss of superficial sensitivity or sense oftouch of a human being or another mammal is provided. The SCB issaxitoxin or one of its derivatives, tetrodotoxin or one of itsderivatives or a tricyclic 3,4-propinoperhydropurine represented by thefollowing formula (I)

wherein R₁ and R₅ are independently selected from the group consistingof —H and —OH; R₂ and R₃ are independently selected from the groupconsisting of —H, —OSO₃ ⁻ and —SO₃; and R₄ is selected from the groupconsisting of —H, —OH, —COONH₂, —COONHSO₃ ⁻ and —COOCH₃.

The sodium channel blocker may be administered over a period of betweenone to seven days and/or in multiple treatment cycles. By “superficialsensitivity” the ability of the human being or other mammal to registerexternal stimuli like heat, cold or pressure on its skin or mucosa ismeant. By “sense of touch” any ability of the human being or othermammal to register a touch is meant. The sense of touch is a specificsuperficial sensitivity. A reduction or loss of superficial sensitivityis often felt as numbness. The reduction or loss of superficialsensitivity or sense of touch is a pathological condition that may becaused by a pathogen, by a medical treatment such as chemotherapy or raytreatment, under which it may occur as side effect, by the use ofweapons, or by a nuclear accident.

The inventors of the present invention have recognized that a reductionor loss of superficial sensitivity or sense of touch can be treated withan SCB according to the invention such that the superficial sensitivityor the sense of touch is at least partly restored. For example, indiabetes mellitus there is a loss of superficial sensitivity in theextremities. This loss of superficial sensitivity can be treated with anSCB according to the invention such that sensitivity will be restored.

The effect of recovery of sensitivity is independent of the presence ofpain such as a neuropathic pain. This means that the effect is not justowing to a possibly also occurring suppression of pain that withouttreatment drowns out every other feeling. The treatment of a reductionor loss of superficial sensitivity or sense of touch is different fromthe known treatment of neuropathic pain with SCBs.

The effect of the treatment is also totally different from the effect ofa treatment of neuropathic pain with a local anesthetic such aslidocaine which is also an SCB. If pain caused by neuropathy is treatedwith lidocaine, pain and sensitivity are lost in the area innervated bynerves affected by the treatment. During treatment with lidocaine theloss of sensitivity lasts as long as the pain relief. The superficialsensitivity and sense of touch restoring activity of the SCB accordingto the invention is a complete new effect. This effect is totallysurprising because in higher dosages SCBs can totally block thepropagation of action potentials along axons of neurons.

In an embodiment of the invention either one of R₂ and R₃ is —OSO₃ ⁻ orR₄ is —COONHSO₃ ⁻. The tricyclic 3,4-propinoperhydropurine may be one ofthe derivatives of saxitoxin or a gonyautoxin (hereinafter “GTX”)according to formula I as set forth in the table below.

Compound R₁ R₂ R₃ R₄ R₅ Gonyautoxin 1 —OH —H —OSO⁻ ₃ —COONH₂ —OHGonyautoxin 2 —H —H —OSO⁻ ₃ —COONH₂ —OH Gonyautoxin 3 —H —OSO⁻ ₃ —H—COONH₂ —OH Gonyautoxin 4 —OH —OSO⁻ ₃ —H —COONH₂ —OH Gonyautoxin 5 —H —H—H —COONHSO⁻ ₃ —OH Neosaxitoxin —OH —H —H —COONH₂ —OH Descarbamoyl- —OH—H —H —OH —OH saxitoxin

In one embodiment the SCB according to the invention is in the form ofits racemate, pure stereoisomer, especially enantiomer or diastereomeror in the form of a mixture of stereoisomers, especially enantiomers ordiastereomers, in neutral form, in the form of an acid or base or in theform of a salt, especially a physiologically acceptable salt, or in theform of a solvate, especially a hydrate.

The reduction or loss of the superficial sensitivity or sense of touchmay be a side effect of a drug or of a medical treatment or may becaused by diabetes mellitus, a viral infection, in particular a Herpesvirus infection or a Varizella-Zoster virus infection, allodynia,causalgia, hyperalgesia, hyperesthesia, hyperpathia, neuralgia,neuritis, neuropathy or other neurologic cause.

In one embodiment the SCB according to the invention is saxitoxin or oneof its derivatives, wherein the saxitoxin or the derivative issynthetically synthesised or isolated from a biological source, inparticular from cyanobacteria or from contaminated shellfish, especiallyshellfish contaminated with A. catenella.

The SCB according to the invention may also be tetrodotoxin or one ofits derivatives or the tricyclic 3,4-propinoperhydropurine, wherein thetetrodotoxin, the derivative, or the tricyclic 3,4-propinoperhydropurineis synthetically synthesised or isolated from a biological source. Incase of tetrodotoxin the biological source may be a puffer fish.

The invention further concerns a pharmaceutical composition comprisingat least one sodium channel blocker according to the invention and apharmacologically acceptable carrier. The carrier may be any materialsuitable for topical drug administration. Carriers include any suchmaterials known in the art which is non-toxic in the amount used, anddoes not interact with other components of the composition indeleterious manner.

In an embodiment the SCB according to the invention is contained in thepharmaceutical composition in an amount suitable for an administrationof 0.01 to 1000 μg, in particular 0.1 to 100 μg, especially 1 to 10 μg,SCB per day. The SCB according to the invention may be contained in thepharmaceutical composition in a concentration of 0.01 to 1000 μg per ml,in particular 0.1 to 100 μg per ml, especially 1 to 10 μg per ml.

The pharmaceutical composition according to the invention may be apharmaceutical composition prepared for injection, in particularintramuscular, intravenous, intradermal, or subcutaneous injection,prepared for topical administration, in particular superficialadministration, or prepared for systemic administration, in particularoral administration.

The pharmaceutical composition prepared for superficial administrationcan be a skin-patch, a cream, an ointment, or a spray. Theadministration may be supported physically in particular by UV light,ultra sound, iontophoresis, phonophoresis, or mechanical modulation.

According to an embodiment of the invention the pharmaceuticalcomposition further comprises at least one analgesic compound. Theanalgesic compound can be lidocaine or one of its derivatives,bupivacaine or one of its derivatives, fentanyl or one of itsderivatives, or acetaminophen or one of its derivatives.

The SCB in the pharmaceutical composition according to the invention maybe contained in a liposome or a microemulsion. A microemulsion is astable, isotropic liquid mixture of oil, water and surfactant,frequently in combination with a cosurfactant. The mixture is anemulsion with oil dispersed in water or water dispersed in oil thedispersed phase of which is forming such small domains that visiblelight is not scattered by the dispersed phase. Therefore, themicroemulsion is clear.

Alternatively or in addition the pharmaceutical composition comprisingthe SCB may further comprise at least one substance facilitating thetransport of the SCB through the skin. Such substances are known in theart as permeation enhancers. The substance may be a substance selectedfrom the group consisting of: alcohols, amines, amides, amino acids,amino acid esters, 1-substituted azacycloheptan-2-ones, pyrrolidones,terpenes, fatty acids, fatty acid esters, macrocyclic compounds,tensides, sulfoxides, liposomes, transferomes, lecithin vesicles,ethosomes, anionic, cationic and non-ionic surfactants, polyols,essential oils, dimethylsulfoxide, decylmethylsulfoxide, diethyleneglycol monoethyl ether, diethylene glycol monomethyl ether, sodiumlaurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,benzalkonium chloride, a poloxamer, polysorbate 20 (Tween20=polyoxyethylene sorbitan monolaurate), polysorbate 40 (Tween40=polyoxyethylene sorbitan monopalmitate), polysorbate 60 (Tween60=polyoxyethylene sorbitan monostearate), polysorbate 80 (Tween80=polyoxyethylene sorbitan monooleate), lecithin,1-n-dodecylcyclazacycloheptan-2-one, ethanol, propanol, octanol, benzylalcohol, lauric acid, oleic acid, valeric acid, isopropyl myristate,isopropyl palmitate, methylpropionate, ethyl oleate, sorbitansesquioleate, propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, polyethylene glycol monolaurate, urea,dimethylacetamide, dimethylformamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanol amine, diethanol amine, triethanolamine,alkanones, salicylic acid, salicylates, citric acid and succinic acid.

The poloxamer (polyethylene-polypropylene glycol, molecular formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H, wherein a and b are integers) is asynthetic nonionic triblock block copolymer composed of a centralhydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked bytwo hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). It isavailable in several types such as Poloxamer 231, Poloxamer 182, orPoloxamer 184.

The invention further concerns a method of treatment of a reduction orloss of superficial sensitivity or sense of touch of a human being oranother mammal, wherein the SCB or the pharmaceutical compositionaccording to the invention is administered to the human being or othermammal

EXAMPLE

The following cream composition was used for all therapeuticapplications described below:

Ingredient Concentration Aqua 70.400 Persea Gratissima Oil 6.000Propylene Glycol 5.000 Squalane 3.500 Active Ingredient xx Petrolatum3.500 Dimethicone 3.000 PEG-20 Methyl Glucose Sesquistearate 2.500 CetylAcetate and Acetylated Lanolin Alcohol 2.000 (total concentration of thementioned ingredients) Diazolinidyl Urea and Methylparaben and 1.500Propylparaben and Propylene Glycol (total concentration of the mentionedingredients) Glyceryl Stearate 1.000 Methyl Glucose Sesquistearate 0.500Triethanolamine 0.300 Ozokerite 0.300 Carbomer 0.050 Acrylate(s) 0.200Parfum 0.150 Tocopherol and Ascorbyl Palmitate and Lecithin and 0.100Glyceryl Stearate and Glyceryl Oleate and Citric Acid

The concentrations in the above table are given in grams of a total of100 g. The acrylate(s) may be C 10-30 alkyl acrylate crosspolymer(s)

1. Active Ingredient: 10 μg/ml of a Mixture of the Epimers GTX-2 andGTX-3

Three patients (2 female, 1 male) used a pharmaceutical compositionaccording to the invention containing 10 μg/ml of a mixture of theepimers GTX-2 and GTX-3. The mixture of GTX-2 and GTX-3 was contained inliposomes in the above-specified cream composition. All three patientswere AIDS patients with drug-related neuropathy. All patients werereceiving a drug combination including a nucleosidereverse-transcriptase inhibitor, didanosine. It is well-known thatpatients on didanosine may develop toxic peripheral neuropathy, usuallycharacterised by bilateral symmetrical distal numbness, tingling, andpain in feet and, less frequently, hands.

All three patients presented numbness and loss of superficialsensitivity in addition to an intense neuropathic pain in their inferiorlimbs (ankles and feet). They described the pain as the worst pain everexperienced preventing them to have a normal sleep and complained thatthey could not feel hot and/or cold in their feet.

The first patient (female, age: 45) presented numbness and loss ofsensitivity in both her feet. She had been treated with anantidepressant drug associated with analgesics. She reported that thepain was poorly controlled with the drugs she received. She began to usethe pharmaceutical composition in the numb area using it once a day thenup to three times a day. She reported feeling better (i.e. a decrease inher symptoms) after using the pharmaceutical composition three timesdaily for three days. After one week of application she reported acomplete relief of the initials symptoms.

The second patient (male, age: 51) presented numbness, loss ofsensitivity and neuropathic pain in both feet and his right calf. He hasbeen treated with antidepressant drug, analgesics and vitamins for hiscondition. He reported no relief of the symptoms with this treatment. Heused the pharmaceutical composition in topical application on theaffected areas four times a day. After four days of application he felta decrease in the symptoms, reporting a complete relief nine days afterhe began to use the composition.

The third patient (female, age: 47) presented loss of sensitivity andneuropathic pain in both feet and calfs. She had been treated withanticonvulsant drug, analgesics, vitamins and acupuncture. The symptomswere so intense that she attempted to stop her AIDS medication. She usedthe pharmaceutical composition on her painful and numb areas three timesdaily. After two days of treatment she reported less pain and numbnessin the affected areas and relief of symptoms ten days after she began.In the meanwhile she resumed her AIDS medications. She attempted to stopthe application of the pharmaceutical composition and reported that thepain and numbness came back within a few days. Resuming the applicationof the pharmaceutical composition resulted in pain relief andsuperficial sensitivity recovery within one week.

All three patients had been treated for their conditions with differentdrugs or drug associations including analgesics, antidepressant oranticonvulsant drugs, vitamins, or physical treatment (acupuncture) withno or few positive results.

They applied the pharmaceutical composition on the numb areas one tofour times per day. They reported a decrease of the symptoms after abouttwo to four days of use and a complete relief within seven to nine days.

A further patient (female, age: 56) used the same cream composition asspecified above containing 10 μg/ml of a mixture of the epimers GTX-2and GTX-3 contained in liposomes.

This patient's history is remarkable by the existence of a grade IIb/IIIcervicouterine cancer in the past years, treated with chemotherapy andradiotherapy. The patient first presented with local pain on theinternal side of the right arm. This pain was described as severe andunbearable, and she reported she almost could not wear clothes. This wasfollowed by a typical zoster distributed skin eruption of an entiredermatoma (posterior and anterior T6). The eruption resolved in abouttwo weeks. The pain lasted about six weeks from the beginning of theclinical presentation. This patient could not be treated withantidepressant or anticonvulsivant agents since she was already treatedwith bupropion for a post-traumatic depression. She was given NSAID(ketoprofen 200 mg twice daily), and acetaminophen (1000 mg three timesdaily). No opiod-like drug (tramadol) could be used due to a patienthistory of intolerance to this drug. She intended to use a topicalpreparation of lidocaine 5% with no or poor relief of the pain.

She began to use the GTX-2 and GTX-3 containing cream compositiontopically about one week after the onset of the symptoms. Relief of thepain and recovery of a normal superficial sensitivity was noted between15 and 30 min after the application, lasting for about 4 to 6 hours. Shecontinued to use the topical GTX preparation three to four times a daywith the same results. In absence of application the patient noted arecurrence of the pain.

2. Active Ingredient: 10 mg/ml Neosaxitoxin

A further patient (male, age: 70) used the same cream composition asspecified above containing 10 μg/ml neosaxitoxin contained in liposomes.

This patient has COPD (Chronic Obstructive Pulmonary Disease) of severalyears of evolution. Its current treatment includes prednisone(corticoid) 5 mg per day, plus inhalers. The patient presented a typicalophthalmic herpes zoster on the right side. The pain was severe andunbearable. He was given NSAID and acetaminophen because no opiods andopiods-like drugs could be used due to his respiratory condition. Hebegan to apply the neosaxitoxin containing cream composition topicallythree days after the onset of the symptoms. He used it three to fourtimes a day obtaining a relief of the pain and a recovery of thesuperficial sensitivity within half an hour after the application. Heused the preparation during two weeks.

1-19. (canceled)
 20. A method of treatment of a reduction or loss ofsuperficial sensitivity or sense of touch of a human being or anothermammal in need thereof, the method comprising topically administering acomposition comprising 1 to 100 μg/ml of a sodium channel blocker (SCB)to the human being or other mammal, thereby treating the reduction orloss of superficial sensitivity or sense of touch of the human being orother mammal, wherein the SCB is neosaxitoxin, descarbamoylsaxitoxin,gonyautoxin 1 (GTX-1), gonyautoxin 2 (GTX-2), gonyautoxin 3 (GTX-3),gonyautoxin 4 (GTX-4), or gonyautoxin 5 (GTX-5), wherein the SCB is inthe form of a racemate, a pure stereoisomer, or a mixture ofstereoisomers, in neutral form, or in the form of an acid, a base, asalt, or a solvate.
 21. The method of claim 20, wherein the compositioncomprises 10 μg/ml of the SCB.
 22. The method of claim 20, wherein thecomposition comprises 1 to 10 μg/ml of the SCB.
 23. The method of claim20, wherein the composition comprises 10 to 100 μg/ml of the SCB. 24.The method of claim 20, wherein the composition is administered as askin-patch, a cream, an ointment, or a spray.
 25. The method of claim20, wherein the SCB is contained in a liposome or a microemulsion, orwherein the pharmaceutical composition further comprises at least onesubstance facilitating the transport of the SCB through the skin,wherein the substance is selected from the group consisting of alcohols,amines, amides, amino acids, amino acid esters, 1-substitutedazacycloheptan-2-ones, pyrrolidones, terpenes, fatty acids, fatty acidesters, macrocyclic compounds, tensides, sulfoxides, liposomes,transferomes, lecithin vesicles, ethosomes, anionic, cationic andnon-ionic surfactants, polyols, essential oils, dimethylsulfoxide,decylmethylsulfoxide, diethylene glycol monoethyl ether, diethyleneglycol monomethyl ether, sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, a poloxamer,polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 40(polyoxyethylene sorbitan monopalmitate), polysorbate 60(polyoxyethylene sorbitan monostearate), polysorbate 80 (polyoxyethylene5 sorbitan monooleate), lecithin, 1-n-dodecylcycla-zacycloheptan-2-one,ethanol, propanol, octanol, benzyl alcohol, lauric acid, oleic acid,valerie acid, isopropyl myristate, isopropyl palmitate,methylpropionate, ethyl oleate, sorbitan sesquioleate, propylene glycol,ethylene glycol, glycerol, butanediol, polyethylene glycol,poly-ethylene glycol monolaurate, urea, dimethylacetamide,dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanol amine,diethanol amine, triethanolamine, alkanones, salicylic acid,salicylates, citric acid and succinic acid.
 26. The method of claim 20,wherein the SCB is contained in a liposome or microemulsion.
 27. Themethod of claim 20, wherein the SCB is contained in a liposome.
 28. Themethod of claim 20, wherein the method comprises administering thecomposition in multiple treatment cycles.
 29. The method of claim 20,wherein the method comprises topically administering the composition oneto four times a day.
 30. The method of claim 20, wherein the methodcomprises topically administering 10 to 1000 μg of the mixture per day.31. The method of claim 20, wherein the method comprises topicallyadministering 10 to 100 μg of the SCB per day.
 32. The method of claim20, wherein the reduction or loss of the superficial sensitivity orsense of touch is a side effect of a drug or of a medical treatment oris caused by diabetes mellitus, a viral infection, allodynia, causalgia,hyperalgesia, hyperesthesia, hyperpathia, neuralgia, neuritis, orneuropathy.
 33. The method of claim 20, wherein the administering issupported physically by UV light, ultrasound, iontophoresis,phonophoresis, or mechanical modulation.
 34. The method of claim 20,wherein each of the SCBs independently is synthetically synthesized orisolated from a biological source.
 35. The method of claim 34, whereinthe biological source is cyanobacteria or contaminated shellfish.
 36. Amethod of treatment of a reduction or loss of superficial sensitivity orsense of touch of a human being in need thereof, the method comprisingtopically administering a composition comprising 1 to 10 μg/ml of asodium channel blocker (SCB) to an area of the human being in whichthere is a reduction or loss of superficial sensitivity or sense oftouch, thereby treating the reduction or loss of superficial sensitivityor sense of touch of the human being, wherein the SCB is neosaxitoxin,descarbamoylsaxitoxin, gonyautoxin 1 (GTX-1), gonyautoxin 2 (GTX-2),gonyautoxin 3 (GTX-3), gonyautoxin 4 (GTX-4), or gonyautoxin 5 (GTX-5),wherein the SCB is in the form of a racemate, a pure stereoisomer, or amixture of stereoisomers, in neutral form, or in the form of an acid, abase, a salt, or a solvate.
 37. The method of claim 36, wherein thecomposition comprises 10 μg/ml of the SCB.
 38. The method of claim 36,wherein the composition is a cream composition and the SCB is containedin a liposome.